Browsing by Author "Pandithavidana, D. R."

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Comparative study of antidiabetic potential of major phytochemicals in bitter melon (Momordica charantia): Computational insights
(Faculty of Science, University of Kelaniya Sri Lanka, 2024) Prasangika, F. N.; Pandithavidana, D. R.
Diabetes mellitus is one of the most common diseases that can be found in both developed and developing countries. The fruit of bitter melon, Momordica charantia is popular among Asians because of its significant antidiabetic potential. The human GSK-3 protein is known to phosphorylate and inactivate glycogen synthase, which is utilized as a negative regulator in the hormone-regulated maintenance of glucose homeostasis. The antidiabetic substances (Charantin, Vicine, Momordenol, and Momordicilin) which derived from bitter melon activate glycogen synthase by blocking the active site of the GSK-3 protein. These ligands enhance insulin sensitivity and promote glucose uptake into the cell. This research was aimed to investigate and compare the binding affinities of these antidiabetic phytochemicals with the GSK-3 protein. The molecular structures of the ligands were retrieved from the PubChem database. Ligands were optimized geometrically using the density functional theory with B3LYP functional and 6-311G++ (d, p) basis set, employing software of Gaussian-09. The 3D structures of GSK-3 protein molecules were downloaded from the Protein Data Bank (PDB ID: 1Q5K). It contains both isoforms, GSK-3α and GSK-3β. The Lamarckian genetic algorithm was used for docking studies using AutoDock 4.2. Molecular interactions between protein-ligand (antidiabetic substances) complexes, bond lengths, and amino acids in binding pockets were analyzed by using the Discovery Studio. Among these four anti-diabetic substances used for this computational study, Momordenol, with the highest binding affinity (-9.91 kcal/mol) for GSK-3 protein, forms a strong and stable complex with the protein. This strong binding enhances its inhibition efficacy by preventing GSK-3 from functioning effectively, leading to greater inhibition potential. In this study, we also compared the binding energies and inhibition constants of N-(4-Methoxybenzyl)-N'-(5-Nitro-1,3- Thiazol-2-Yl) Urea (AR-A014418), a known GSK-3 inhibitor (-7.59 kcal/mol, 2.74 µM), with Momordenol (-9.91 kcal/mol, 0.05411 µM), Momordicilin (-9.51 kcal/mol, 0.10359 µM), Charantin (- 8.49 kcal/mol, 0.59355 µM), and Vicine (-6.71 kcal/mol, 11.99 µM). The results show that Momordenol has the strongest binding affinity and the lowest inhibition constant, indicating superior inhibitory potential. By using AR-A014418 as a reference, this comparison highlights Momordenol as a promising therapeutic candidate for targeting GSK-3 protein, offering potential advantages in drug development. The comparative study exhibited the anti-diabetic potential of these four major phytochemicals present in the fruit of bitter melon follow the order of Momordenol > Momordicilin > Charantin > Vicine. These computational insights encourage the design of structurally novel antidiabetic substances which will be more economical and beneficial in the pharmaceutical industry.
Comparative study of antidiabetic potential of major phytochemicals in Sri Lankan Thebu (Costus speciosus): Computational insights
(Faculty of Science, University of Kelaniya Sri Lanka, 2024) Karunaratne, A. D. N. A.; Pandithavidana, D. R.
In the 21st century's most rapidly expanding health concern worldwide is diabetes. Type 2 diabetes is a major public health concern and is more prevalent than Type 1. Costus speciosus (Thebu) has been known as the insulin plant containing several numbers of bioactive, phytoconstituents. This computational research study was focused on investigating the mechanistic activity of some antidiabetic compounds (Diosgenin, Costunolide & Eremanthin) available in Thebu. Molecular structures were screened from a PubChem database and corresponding protein crystal structures of Alphaamylase(4GQR), Alpha-glucosidase(2QMJ), Protein Tyrosine Phosphatase 1B(2QBP), and Inducible Nitric oxide synthase(4NOS) were retrieved from the protein data bank. The structures were optimized using the density functional theory method with B3LYP functional and 6-311G++ (d, p) basis set. The scoring function of Autodock 4.2.6 was used to determine the docked compounds' binding free energies and, for accurate results, six docking trials were carried out for each protein-ligand complex using the genetic algorithm. In this research, Acarbose and Lobeglitazone have been used as standard reference drugs for comparison with new ligand structures. The results of computational docking studies revealed these three ligands bound with all four proteins as providing binding energies, in the range between -6 to -11 kcal/mol while, diosgenin exhibited the lowest binding energies (more negative) with all four proteins as demonstrating the highest affinity with Alpha-amylase (-9.36 kcal/mol), Alpha-glucosidase (-9.79 kcal/mol), Tyrosine phosphatase 1B (-9.33 kcal/mol) and Inducible Nitric-oxide Synthase (- 10.43 kcal/mol). Further, the inhibition constant, Ki of diosgenin with four proteins revealed lower values as concluding that diosgenin has a greater inhibition of diabetic-related proteins. Eremanthin with Alpha-glucosidase, NOS also demonstrated a lower binding energy and a lower inhibition constant. A smaller inhibition constant relates to a stronger inhibitory potential, while lower binding energy values indicate a higher binding affinity of ligands with the proteins. These investigations positively supported the hypothesis that Costus speciosus might have an antidiabetic effect involved in the binding of these phytoconstituent ligands to their proteins. The affinity order of binding these phytochemicals into the four types of proteins exhibited as Costunolide < Eremanthin < Diosgenin. In conclusion, these computational insights encourage the design of structurally novel pharmaceuticals.
Computational insight into the antioxidant mechanisms of major catechins found in cocoa: DFT study
(Faculty of Science, University of Kelaniya, Sri Lanka, 2021) Sandaruwan, W. A. M.; Pandithavidana, D. R.
Among diverse classes of antioxidants, polyphenolic compounds exhibit important chain- breaking properties to quench reactive radical species which are generated during the oxidative processes of both commercial and biological products. Antioxidants as external supplements are used to maintain the concentration of free radicals as low as possible and to avoid oxidative stress. They are profoundly utilized in the food manufacturing to preserve the quality of the ready-to-eat foods and to improve the shelf life. Among the polyphenolic food products, cocoa is rich in catechins. The three major catechins available in cocoa are (+)-epicatechin, (-)-catechin and dimeric procyanidin. Computational studies of density functional theory (DFT) have been accomplished to explore the antioxidant potential of these catechin molecules. Reaction enthalpy values related to three key mechanisms of basic antioxidant pathways; [1] hydrogen atom transfer (HAT), [2] single-electron transfer - proton transfer (SET-PT), and [3] subsequent proton loss- electron transfer (SPLET) were computationally investigated using B3LYP/ 6-311++G (d, p) and M062X/ 6-311++G (d, p) level of theory. The aqueous phase studies were carried out under the IEFPCM solvation model. The hardness, softness, electronegativity and electrophilicity of antioxidants were computed using HOMO-LUMO energy calculations. According to these computational investigations, it was revealed that the HAT mechanism has demonstrated the lowest set of enthalpies compared to other two reaction mechanisms (SET-PT and SPLET). It was positively obvious that dimeric procyanidin possessed the lowest set of average enthalpies as showing the highest antioxidant potential with compared to the other two catechins. Based on average enthalpies, antioxidant potential of catechins found in cocoa can be placed in the following order of ascending: (-)-epicatechin < (+)-catechin < dimeric procyanidin. Energies of molecular orbitals (EHOMO–LUMO) present in these three natural catechins exhibited that dimeric procyanidin molecule has possessed the highest radical scavenging capability as further verifying the “trend of antioxidant potential” observed under the thermodynamic parameters (BDEs, IPs, PDEs, PAs and ETEs) previously computed. It can be concluded that modification of the chemical structure of dimeric procyanidin provides insight into the design of structurally novel, potent antioxidants which will be more economical and beneficial in pharmaceutical industry.
Computational investigation of pesticide induced oxidative stress and its impact on the Chronic Kidney Disease of unknown etiology (CKDu)
(International Journal of Science, Environment and Technology, 2019) Pandithavidana, D. R.; Deshan, T. M. V.
The chronic kidney disease of unknown etiology (CKDu) has been a major health issue in Sri Lanka within the last three decades. Many investigative efforts have been carried out to identify its unknown origin and several risk factors which have been associated. A possible link between oxidative stress and the progression of the disease has been identified. The environmental factors which favor the development of oxidative stress are prevalent in those affected areas. The study of “pesticide induced oxidative stress” has been a topic of research interest. Alterations in the balance between the production of free radicals and the antioxidant defenses were recognized as one of the main causes. Four major pesticides were docked with different enzymes which directly related to mechanisms in generating oxidative stress, using Auto Dock molecular docking program. The strength of the binding of the pesticide in the binding site of the corresponding enzyme was used to emphasize its potential interaction with Cytochrome P450 A34enzyme. According to molecular docking investigations, it was evident that three organophospahates; Profenofos, Diazinon and Chlrofyrifos possessed relatively similar binding energies at the active site compared to the inducer for Cytochrome P450 A34 enzyme. These organophosphates behave as the potent enzyme inducers as well as substrates which involved in bio-activation. The computational findings directed to disclose how reactive oxygen species were generated to cause oxidative stress and it can be utilized to predict mechanistic steps related to the pesticide induced oxidative stress.
Computational Investigation of Structural, Electronic and Thermodynamic Properties of Nonylphenolethoxylate Surfactants
(International Journal of Science, Environment and Technology, 2019) Pandithavidana, D. R.; Jayalath, W. I. M.
Nonylphenol ethoxylates (NPEs) are group of non-ionic surfactants commonly known as Tergitol NP surfactants. The hydrophilic-lipophilic-balance (HLB value) is used as the key parameter by surfactant formulators to study the properties of non-ionic surfactants. Even though the HLB values of two surfactants are equal or close enough to each other, the expected properties cannot be obtained by replacing one surfactant with another one. This issue leads to a necessity to carry out many trial and error tests to identify the equivalent surfactants in industrial applications. The strong hydrogen bonding with water, Gibbs free energy change of solvation (ΔGsolv), molecular dipole moment and maximum absorption wavelength (λmax) have been developed as key performance indicators of a better surfactant in this research work. Computed results predict that NPEs are well stabilized in the aqueous medium with the extension of ethoxylate chain length, illustrating a linear relationship of ΔGsolv with respect to the number of ethylene oxide units. This evidence has been further supported by the decrease in hydrogen bond length, between the NPEs and water molecules with the extension of the ethoxylate chain of the surfactant. Among ortho- , meta-, and parasubstituted NPEs, due to the presence of higher dipole moments of meta-substituted NPEs indicated that they form more efficient secondary interactions in aqueous medium. Moreover meta-substituted NPEs demonstrate relatively higher thermodynamic stability (than ortho- and para- substituted NPEs) due to the presence the highest HOMO-LUMO gap.
Computational investigation of the structural and thermodynamic properties of nonylphenol ethoxylate surfactants.
(International Research Symposium on Pure and Applied Sciences, 2017 Faculty of Science, University of Kelaniya, Sri Lanka., 2017) Narthani, B. D. S.; Pandithavidana, D. R.
The word “sufactant” has originated from the three words “surface active agents.” Surfactants are compounds that have potential to lower the surface tension (or interfacial tension) between two liquids or between a liquid and a solid. Nonylphenol ethoxylates (NPEs) are a group of non-ionic surfactants commonly known as Tergitol NP surfactants. Nonylphenol ethoxylates are classified according to the number of ethoxylate units in the hydrophilic chain. The properties of the nonylphenol ethoxylates differ with the number of ethoxylate units in the molecule. The hydrophilic–lipophilic-balance (HLB value) is the key parameter that the surfactant formulates are focused on when studying the properties of non-ionic surfactants. Even though the HLB values of two surfactants are equal or close enough to each other, the expected properties cannot be obtained by replacing one surfactant with another one. This issue leads to the necessity to carry out many trial and error tests to identify the equivalent surfactants in industrial applications. To address this issue, a comprehensive investigation of the nonylphenol ethoxylate molecules was carried out computationally at B3LYP level of theory using 6-311G basis set in Linux version of Gaussian 09 computer software package. The aqueous phase investigation focused on deducing the interactions between nonylphenol ethoxylates and water with extending the chain length of ethoxylate part, branching the nonyl hydrocarbon chain and varying the substituent position (-ortho, -meta and -para) of nonylphenol ethoxylate molecules. To interpret the interactions of nonylphenol ethoxylate molecules with water, molecular properties such as Gibbs free energy changes of solvation (ΔGsolv) in aqueous medium, molecular dipole moments and hydrogen bond lengths between surfactant molecules and water molecules were investigated. The more negative values (-46.62 to -116.88 kJ/mol) of the solvation Gibbs free energy (ΔGsolv) indicated that stability of the NPEs in aqueous medium increases with the extension of the length of ethoxylate chain (4 to 16 ethoxylate units). The substituent position and the branching of the nonyl-hydrocarbon chain have not caused a change in Gibbs free energy of solvation significantly. Although electrical dipole moment of NPEs in aqueous medium varied with the position of the substituents, it was not affected by branching patterns of nonyl hydrocarbon group. Computationally simulated UV-Visible spectra of NPEs revealed the absorption maximum of NPEs ( λmax) was independent of ethoxylate chain length. UV-Visible spectra generated from selected molecules of NPEs confirmed that absorption maximum ( λmax) of the surfactant species was significantly affected by the change in position of substituents.
Development and validation of an analytical method to detect Monosodium Glutamate in food samples and analysis of MSG in selected Sri Lankan food products
(Faculty of Science, University of Kelaniya Sri Lanka, 2023) Sithumini, D. D.; Pandithavidana, D. R.; Thambavita, T. M. D. D.
Monosodium glutamate (MSG) is a synthetic flavour enhancer commonly used in the food industry, even though it comes from a natural source. Although MSG is commonly utilized as a food additive to improve taste, it has been linked to various health problems in humans. The potential health effects that have been associated with MSG include Chinese restaurant syndrome, asthma and respiratory reactions, migraine headaches, and allergic reactions. Researchers have conducted studies on animals to explore the effects of consuming MSG. Use of MSG in foods has been regulated in many countries. Although the food regulations of Sri Lanka clearly provide for the type of foods that MSG is not permitted, analytical facilities are not available in the country for quality assurance. In this study, a liquid chromatography-tandem mass spectrometry (LCMS/MS) method was developed and validated to quantitatively analyze MSG and determine its presence in selected food products available in Sri Lanka based on the food regulations. The food products were purchased from supermarkets and they included seasoning cubes, seasoning powders, biscuits, chips, sauces, and soups. Separation of MSG was done using a C-18 column with mobile phase A (0.1% formic acid in type 1 water) and mobile phase B (acetonitrile) with the isocratic elution (A:B 30:70). Retention time of MSG was 2.5 min. The specific glutamate ion transitions detected were 148.00 to 84.00, 102.00, and 130.00 m/z. Key analytical parameters were validated according to the ICH guidelines. The method was linear in the range of 0.50-10.00 mg/L, with a correlation coefficient (R2 ) of 0.9994 and was accurate between ±5% range from the true value. The CV% values of 4.99%, 1.71% and 0.94% for three concentration levels (0.5 ppm, 2.5 ppm and 10.0 ppm respectively) that covered the calibration series obey the accepted criteria of
Exploring the MSG related metabolic mechanisms through computational docking
(Faculty of Science, University of Kelaniya Sri Lanka, 2022) Dananjaya, P. D. H.; Pandithavidana, D. R.
Monosodium Glutamate (MSG), also known as Ajinomoto is a widely used flavour enhancer in various food industries. Glutamate is the major component of the MSG which is produced within the human body. Also, it acts as an excitatory neurotransmitter within the central nervous system. Because of the characteristics of umami taste-producing capability, various foods contain MSG as a food additive. Normally in the market, it is known as E621 flavour enhancer. Among L and D enantiomers only L enantiomer has the flavour enhancing property because of the stimulation of the taste receptors. Even taste-enhancing properties, there are some health problems associated with the monosodium glutamate in the human. Triggering of obesity, diabetes, neurotoxicity (neurological disorders such as Alzheimer, Parkinson, Sclerosis), hepatotoxicity, oxidative kidney damage, headache, sweating, numbness, chest pain, and nausea are mainly associated with the consumption of higher amount of MSG containing foods. Various animal-based trials were performed already to find out the effect of MSG under different laboratory conditions. Computational docking was used to investigate the synergistic effect between monosodium glutamate (MSG) and the receptor proteins and metabolic enzymes. Before the docking step, the glutamate ligand was energetically optimised by using the Gaussian 09 software and the 3D structures of selected receptors and enzyme modeled via the SWISS-MODELER. Also, the proteins were refined by the Galaxy Refiner. The results showed specific changes upon the interaction of MSG with xenobiotic-metabolizing enzymes (CYP2E1), xenobiotic sensing receptor (CAR), GLP-1 receptor, mGlu5 receptor in terms of energy and conformation. The mGlu5 receptor exhibited the most favourable binding interactions with MSG due to the presence of both polar and non-polar amino acids in the binding pocket of receptor. Ser152 tends to form strong hydrogen bonds with the glutamate ligand. Five residues in the binding pocket Ser173, Gly150, Ala174, Tyr223 and Trp100 played critical roles in forming hydrophobic interactions. Also, Gln234, Lys197 and Arg310 was observed as H bond forming amino acids with the glutamate ligand in the GLP-1 receptor. As well as CYP2E1 showed a considerable binding affinity for the glutamate ligand in MSG. The receptor proteins and enzymes, which consisted of non-polar functional groups, demonstrated the lowest docking energy and docking interaction energies. This computational study provides an insight into discovering umami-enhancing compounds and how they may interfere/ interrupt natural metabolisms.
Molecular docking studies to identify secondary metabolites present in Ashwagandharishta and their effectiveness towards memory related disorders
(Global Journal of Engineering Science and Research Management, 2019) Pandithavidana, D. R.; Munaweera, R. K. W.
Ashwagandharishta is a famous Ayurveda medicine (in Asian countries) that is used to treat psychiatric conditions, dullness, memory related diseases, anxiety, schizophrenia sluggishness, epilepsy, depression and etc. Memory defects are closely allied with imperfect cholinergic neurotransmission. Repairing mechanisms for theses impaired processes afford promising treatment strategies for these kinds of disorders. Alpha-7 nicotinic acetylcholine receptor is a sub type of nicotinic acetylcholine receptor which has been recognized as one of the most useful drug target for the treatment of nervous system associated disorders. Molecular docking analyses have been carried out to detect any possible secondary metabolites present in Ashwagandharishta that could act as agonists of alpha-7 nicotinic acetylcholine receptor. According these computational findings, it has been found that two phytochemicals; anaferine and anahygrine exhibit promising agonistic activity towards the receptor. Thus anaferine and anahygrine have high possibility to serve as alpha-7nAChR agonists which demonstrate potential drug action towards memory related disorders.